Biology subjects

Giannone, F.

Publications and source records attributed to Giannone, F..

3 recordsLinked to original sources

bioRxiv2022

A Systematic Review and Meta-analysis on the Transcriptomic Signatures in Alcohol Use Disorder- a Translational Approach

Alcohol use disorder (AUD) is a complex mental health condition. Currently available clinical treatments exhibit limited efficacy and new druggable targets are required. One promising approach to discover new molecular treatment targets involves the transcriptomic profiling of brain regions within the addiction neurocircuitry, utilizing animal models and post-mortem brain tissue from deceased AUD patients. Unfortunately, such studies suffer from large heterogeneity and small sample sizes. To address these limitations, we conducted a cross-species meta-analysis on transcriptome-wide data obtained from brain tissue of AUD patients and animal models. We integrated 36 cross-species transcriptome-wide RNA-expression datasets with an alcohol-dependent phenotype vs. controls, following the PRISMA guidelines. In total, we meta-analyzed 1,000 samples - 502 samples for the prefrontal cortex (PFC), 318 nucleus accumbens (NAc) samples, and 180 amygdala (AMY) samples. The PFC had the highest number of differentially expressed genes (DEGs) across rodents, monkeys, and humans. Commonly dysregulated DEGs pointed towards enrichment in inflammatory responses and alterations in BBB-regulatory mechanisms in astrocytes, microglia and endothelial cells. Gene set enrichment analysis further showed that MAPK/ERK-signaling plays a critical role in AUD and especially in monkeys Dusp4 as a major inhibitor of the MAPK pathway may be a main driver of these pathway alterations. Our data also suggest that the transcriptomic profile in the NAc is less vulnerable to the maintenance of AUD. Finally, we provide a combination of DEGs that are commonly regulated across different brain tissues as potential biomarker for AUD. In summary, we provide a compendium of genes, signaling pathways, and physiological and cellular processes that are altered in AUD and that require future studies for functional validation.

neuroscience↗

bioRxiv2022

Generalized habitual tendencies in alcohol dependent rats

Habitual responses and ultimately compulsive behavior are thought to be at the core of addiction including alcohol use disorder (AUD). Little is known whether the habitization concerns exclusively the response towards alcohol or generalizes to other daily activities. Here, we address this question in a well-established animal model of AUD - the postdependent rat model - by testing habitual responses towards a sweet palatable reward in two striatal learning paradigms: spatial navigation and reward conditioning. For the spatial navigation task, alcohol-dependent and control rats were tested on a sequential decision-making test after short and prolonged T-Maze training; for the reward conditioning task, rats were trained under a random interval schedule for a short and prolonged period and tested in a satiety devaluation test at each time point. Another cohort of alcohol-naive rats was trained and tested on both paradigms under DREADD (designer receptors exclusively activated by designer drugs)-mediated inactivation of the dorsomedial striatum (DMS) which controls goal-directed behavior. Our results show that alcohol-dependent rats displayed increased habitual behavior to obtain saccharin reward on both paradigms, with overall more habitual choices after prolonged training on the spatial navigation task, and increased habitual responses already after short training on the reward conditioning task. Finally, DREADD-mediated inactivation of the DMS increased habitual behavior in non-dependent rats on both paradigms. Our results provide evidence that a history of alcohol dependence produces a bias towards habitual responding that generalizes to a natural reward in rats. Similarly, a habitual bias was induced in non-dependent rats after inactivation of the DMS, thus confirming the critical role of this region in maintaining goal-directed behavior and suggesting its diminished control in AUD.

neuroscience↗

bioRxiv2022

Chronic alcohol intake regulates expression of SARS-CoV2 infection-relevant genes in an organ-specific manner

Chronic alcohol consumption and alcohol use disorder (AUD) have a tremendous impact on the patients psychological and physiological health. There is some evidence that chronic alcohol consumption influences SARS-CoV2 infection risk, but the molecular mechanism is unknown. Here, we generated expression data of SARS-CoV2 infection relevant genes (Ace2, Tmprss2 and Mas) in different organs in rat models of chronic alcohol exposure and alcohol dependence. ACE2 and TMPRSS2 represent the virus entry point whereas Mas is activating the anti-inflammatory response once the cells are infected. Across three different chronic alcohol test conditions, we found a consistent upregulation of Ace2 in the lung, which is the most affected organ in Covid-19 patients. Other organs such as liver, ileum, kidney, heart, and the brain showed also up-regulation of Ace2 and Mas but in a less consistent manner across the different animal models, while Tmprss2 was unaffected in all conditions. We suggest that alcohol-induced up-regulation of Ace2 can lead to an elevated stochastic probability of cellular virus entry and may thus confer a molecular risk factor for a SARS-CoV2 infection.

pharmacology and toxicology↗